Prostate cancer is the most commonly diagnosed cancer among men in the United States with more than 241,000 new diagnoses in 2012. Nearly half of the men diagnosed have early stage, low-grade disease, and may be good candidates for active surveillance (AS). AS is an important management option because it reduces overtreatment, including the serious side effects (e.g., incontinence, erectile dysfunction) of standard prostate cancer therapies. However, AS is under-utilized because current clinical tests are imperfect at discerning indolent from aggressive prostate cancer. Furthermore, approximately 15% of men who initially opt for AS ultimately seek curative treatment in the absence of biological progression, due to the anxiety and stress of knowing they have cancer. Hence, identifying strategies that reduce risk of prostate cancer progression and allay AS-specific anxiety could greatly reduce the overtreatment of low risk prostate cancer and benefit public health. We reported that vigorous physical activity and brisk walking after prostate cancer diagnosis were associated with ~60% reductions in prostate cancer progression or death in two distinct cohorts of men with prostate cancer. While compelling, these studies do not address if increasing aerobic exercise after diagnosis favorably alters prostate cancer biology. Our group and others have identified and validated novel prostate genomic signatures that predict poor clinical outcomes among men with low risk prostate cancer, and demonstrated that gene expression in the prostate is modified by short-term lifestyle interventions. Thus, we propose to conduct a randomized controlled trial to evaluate whether 24 weeks of supervised aerobic exercise vs. usual care affects the expression of three validated prostate genomic signatures among 120 men with prostate cancer on AS at the University of California, San Francisco and Duke University. Men assigned to the exercise arm will participate in an individually tailored treadmill-walking program that includes five 30- 45 minute sessions per week at 50-80% of baseline cardiorespiratory fitness (three supervised, two at home). We will also examine the global effects of aerobic exercise on mRNA expression of cancer-related pathways in tumor and normal tissue (e.g. growth factor signaling, angiogenesis, DNA repair); and whether aerobic exercise reduces AS-related anxiety and overall stress compared to usual care. The AS protocol of regular prostate biopsies provides a unique opportunity to study the longitudinal effects of aerobic exercise on prostate cancer biology. The results of this randomized controlled trial will provide the essential evidence needed to support a definitive phase III clinical trial o exercise and prostate cancer progression.